The present invention describes rapid noninvasive methods for measuring vasodilation or changes in blood flow in a patient following administration of at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The method comprises the administration of at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent to the patient followed by monitoring the temperature change of an area of interest using infrared thermography. The present invention provides methods for diagnosing diseases or disorders related to vasodilation and changes in blood flow, such as, sexual dysfunctions, Raynaud""s syndrome, inflammation, hypertension, gastrointestinal disorders and central nervous system disorders. The sexual dysfunction is preferably female sexual dysfunction or female sexual arousal. The vasoactive agents include potassium channel activators, calcium channel blockers, xcex1-adrenergic receptor antagonists, xcex2-blockers, phosphodiesterase inhibitors, adenosine, ergot alkaloids, vasoactive intestinal peptides, prostaglandins, dopamine agonists, opioid antagonists, endothelin antagonists and thromboxane inhibitors. The present invention can also be used to screen and identify drug candidates for treating diseases, disorders and conditions resulting from vasodilation or changes in blood flow. The present invention also describes compositions comprising at least one S-nitrosothiol compound for diagnosing, monitoring and/or treating female sexual dysfunctions.
Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecology and Obstetrics, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the xe2x80x9corgasmic platform,xe2x80x9d an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus occurs. In the male, vasodilation of the cavemosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al, J. Public Health Med., 19(4):387-391 (1997).
While there are obvious differences in the sexual response between males and females, one common aspect of the sexual response is the erectile response. The erectile response in both males and females is the result of engorgement of the erectile tissues of the genitalia with blood which is caused by the relaxation of smooth muscles in the arteries serving the genitalia. This increase in blood flow results in vasodilation and an increase in the temperature of the genitalia tissue.
Methods for evaluating and measuring physiological changes to determine sexual arousal have been previously described. For example, U.S. Pat. Nos. 5,565,466 and 5,731,339 describe the use of Doppler ultrasound velocimetry for measuring vaginal and penile blood flow; Intl. J. Impotence Res., 9:27-37 (1997) discloses the use of photoplethysmorgraphy for monitoring vaginal blood flow; and WO 99/35968 describes devices and methods for monitoring female arousal. These prior art methods are invasive and have major limitations that can effect the accuracy of the measurements.
There is a need in the art for new and improved noninvasive methods for measuring vasodilation and changes in blood flow, and for diagnosing and monitoring diseases related to vasodilation, such as, sexual dysfunctions. The present invention is directed to these, as well as other, important ends.
In arriving at the present invention, it was unexpectedly discovered that the vasodilation or engorgement of the corpus cavemosum smooth muscle, an event involved in the sexual response process in both males and females, results in an increase in temperature that can be monitored by infrared thermography.
One aspect of the present invention describes methods for monitoring and measuring vasodilation and changes in blood flow in patients, by administering to a patient in need thereof at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent, followed by monitoring the temperature change of an area of interest using infrared thermography. Another aspect of the invention comprises the steps of comparing the temperature of the area prior to and after the administration of the nitric oxide donor and/or vasoactive agent. Thus the method may comprise (i) measuring the baseline temperature of an area of interest before exposure to at least one nitric oxide donor and/or vasoactive agent using infrared thermography, (ii) administering to a patient at least one nitric oxide donor and/or vasoactive agent, (iii) measuring the temperature of the area of interest during and/or after administering of at least one nitric oxide donor and/or vasoactive agent using infrared thermography, and (iv) comparing the measurements obtained in steps (i) and (iii), wherein a compound that results in an increase in the temperature is a vasodilator and a compound that results in a decrease in the temperature is a vasoconstrictor. The temperature in step (i) may be a previously obtained stable temperature measurement; or alternatively a measurement taken any time after the administration of the nitric oxide donor and/or vasoactive agent when a stable temperature measurement is obtained. The nitric oxide donors, and/or vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
Another aspect of the invention provides methods for monitoring and diagnosing diseases and disorders related to blood flow, such as, sexual dysfunctions and sexual arousal in patients, preferably males and females, more preferably females, by administering to a patient in need thereof at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent, followed by measuring the temperature of the genitalia using infrared thermography or followed by comparing the temperature of the genitalia after administration of the at least one nitric oxide donor and/or vasoactive agent with a stable baseline temperature measurement obtained using infrared thermography.
Yet another aspect of the invention provides methods for monitoring and diagnosing diseases and disorders resulting from vasodilation and changes in blood flow by administering to a patient in need thereof at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent, followed by comparing the temperature change of the area of interest after administration of the at least one nitric oxide donor and/or vasoactive agent with a stable baseline temperature measurement using infrared thermography. The diseases and disorders resulting from changes in blood flow include Raynaud""s syndrome, inflammation, hypertension, gastrointestinal disorders and central nervous system disorders.
Another aspect of the present invention comprises identification, characterization, rank and selection of compounds that are can be used to treat numerous diseases and disorders resulting from vasodilation and changes in blood flow. For example a test compound may be administered to a patient followed by infrared thermographic measurements of an area of interest to monitor the temperature changes. Compounds that result in a temperature increase are effective for the treatment of the disease or disorder, the greater the increase in temperature, the more potent the compound as a suitable therapy. On the other hand, compounds that produce no temperature change or that result in a temperature decrease are not effective for the treatment of the disease or disorder, the greater the decrease in temperature, the less effective the compound as a suitable therapy.
Yet another aspect of the present invention provides compositions comprising at least one S-nitrosothiol compound and at least one penetration enhancer that may be used to diagnose, monitor and/or treat female sexual dysfunctions. The S-nitrosothiol compound may preferably be S-nitrosoglutathione. The penetration enhancer, may preferably be a glyceride, such as, MIGLYOL(copyright) and/or a polyglycolyzed glyceride, such as, LABROSOL(copyright) and/or LABROFIL(copyright), or a mixture thereof. These compositions may further comprise at least one vascoactive agent and/or at least one nitric oxide donor, or mixtures thereof.
These and other aspects of the present invention are described in detail herein.